A growing body of literature implicates neurogenesis in the potential mechanism of action of antidepressants. However, there is also evidence of behavior that reflects antidepressant efficacy in the absence of neurogenesis. This proposal outlines a series of experiments that will provide insight into the role of neurogenesis in affective disorders. This insight is critical for validating neurogenesis as a drug discovery target to generate more effective relief from the symptoms of depression. Because the etiology of depression is not well understood, and symptoms are often subjective, research is hindered by a lack of animal models which portray the human disease. Rather, animal models often rely on identifying a behavior that is altered or reversed by current antidepressant treatments. Our laboratory has identified a genetic model to temporally reduce hippocampal neurogenesis. Preliminary data indicates that conditional deletion of ataxia-telangeictasia and rad-3 related (ATR), a cell cycle checkpoint kinase, from the hippocampus of the adult mouse, leads to decreased cell proliferation in the dentate gyrus of the hippocampus. Targeting neurogenesis through cell-cycle interference may bypass some confounding side effects of other techniques to reduce neurogenesis, which include x-ray irradiation and methyl-azoxymethanol acetate, a mitotic inhibitor. This grant aims to utilize the Cre-lox conditional ATR knockout mouse to further characterize the effects of hippocampal-specific ATR deletion on hippocampal cell proliferation, maturation, and survival. We will subsequently investigate the effects of ATR deletion in rodent models of depression and antidepressant efficacy. In addition, cellular and behavioral responses to two neurogenic stimuli, antidepressant drugs and voluntary exercise, will be examined following ATR deletion. The overarching goal of this research is to better understand the role of neurogenesis in depression and antidepressant efficacy. Current treatments for depression are ineffective in 30% of patients and induce unwanted side effects due to targeting of specific neurotransmitter systems. Validating neurogenesis as a drug discovery target creates the potential for novel therapeutics in the treatment of depression.